Minimum alveolar concentration

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CHAPTER 62

Minimum alveolar concentration

Anna E. Bartunek, MD

Dosing for most drugs is based on mass of drug per kilogram of patient body weight. However, for inhalation anesthetic agents, the mass of drug and patient weight have little to do with the intensity of the drug effect. Therefore, a method for quantifying the amount of inhalation agent necessary for anesthesia has been devised. Minimum alveolar concentration (MAC) is the alveolar concentration of an inhalation anesthetic agent at 1 atm and at steady-state concentration necessary to suppress a gross purposeful movement in 50% of patients in response to a skin incision.

MAC has been determined in different age groups, under different conditions, and for all inhalation anesthetic agents (Table 62-1), allowing for comparison of the potency of the different agents. MAC is inversely related to anesthetic potency and, therefore, with its lipid solubility (Meyer-Overton theory). MAC is analogous to the pharmacologic effective dose (ED₅₀) of drugs.

Table 62-1

Minimum Alveolar Concentration (MAC) and MAC_awake of Inhalation Anesthetics at Ambient Pressure of 760 mm Hg

	Isoflurane	Desflurane	Sevoflurane	N₂O	Xenon
MAC in O₂ (vol%)	1.3	6.0	2.1	105	71
MAC in 70% N₂O and 30% O₂ (vol%)	0.6	2.5	0.7	—	—
MAC Awake (vol%)	0.4	2.4	0.6	71	33
MAC in O₂ (mm Hg)	9.7	45.6	15.6	798	540

Important concepts related to minimum alveolar concentration

Alveolar concentration

The MAC value of an inhalation anesthetic agent is expressed as a percentage of its alveolar concentration that, at steady state, should approximate the end-tidal concentration, which is measured continuously throughout anesthesia. Alveolar partial pressure of an anesthetic agent is its fractional pressure in the alveolus. The sum of the partial pressures of all components of the alveolar gas mixture equals the total ambient pressure, which is 1 atm or 760 mm Hg at sea level.

Steady state

At equilibrium, the end-tidal concentration approximates the alveolar concentration, which, in turn, approximates the anesthetic concentration at the anesthetic site of action in the central nervous system. Equilibrium is present when end-tidal, alveolar, blood, and brain anesthetic partial pressures are equal. Based on the high cerebral blood flow and low blood solubility of modern anesthetic agents, equilibration is approached after end-tidal concentration has been kept constant for 10 to 15 min. For example, if at sea level and at equilibrium end-tidal N₂O concentration is 60%, then its partial pressure in the alveolus, blood, and brain equals 0.6 atm or 456 mm Hg.

Ambient pressure

MAC values are conventionally given as a percentage of alveolar anesthetic concentration at 1 atm. They either have been determined at sea level or, ideally, have been corrected to sea level when determined at higher altitudes. One has to bear in mind that anesthetic potency and uptake are directly related to the partial pressure of the anesthetic agent (see Table 62-1). At higher altitude, as compared with at sea level, the same concentration of an inhalation anesthetic agent will exert a lower partial pressure within the alveolus and, consequently, a reduced anesthetic effect. Modern variable bypass vaporizers compensate for this effect because, although the dials are marked in “percent,” partial pressure is what is actually determined. At an altitude at which the pressure is one half of sea level, a variable bypass vaporizer set to 1% would deliver 2%, though the actual partial pressure of anesthetic agent delivered would be the same. For example, at sea level, with a barometric pressure of 760 mm Hg, the partial pressure of the agent would be 7.6 mm Hg; at an altitude with a barometric pressure of 380 mm Hg, a variable bypass vaporizer set at 1% would actually deliver 2% of the agent (2% of 380 = 7.6 mm Hg partial vapor pressure).

Stimulus

Skin incision is the standard stimulus used to define MAC in humans. As the intensity of the stimulus decreases, so too does the MAC necessary to block a defined response: intubation > skin incision > tetanic stimulation > laryngoscopy > trapezius squeeze > vocal command.

Response

A positive response, in the classic determination of anesthetic potency, is gross purposeful muscular movement of the head or extremities. Other responses can be eye opening to command or sympathetic adrenergic reaction (increase in blood pressure and heart rate) to noxious stimuli (see later in this chapter).

Determination of minimum alveolar concentration

MAC can be determined in humans by anesthetizing them with the inhalation anesthetic agent alone in O₂ and allowing 15 min for equilibration at a preselected target end-tidal concentration. A single skin incision is made, and the patient is observed for the presence or absence of purposeful movement. A group of patients must be tested in this fashion over a range of anesthetic concentrations that allows and prevents patient movement. The percentage of patients in groups of four or more that show a positive response to surgical stimulation is plotted against the average alveolar concentration for that group. Drawing a best-fit line through these points results in the concentration at which half of the subjects move with skin incision and thus MAC is determined. Another approach is to plot the individual end-tidal anesthetic concentrations against the probability of no response by nonlinear regression analysis. This results in a typical dose-response curve, whereas the concentration that corresponds to the 0.5 probability of no response estimates the MAC value.

Dose-response relationship

The dose-response curve allows for an extrapolation to that anesthetic concentration at which 95% of the patients do not respond to the applied noxious stimulus with movement. Although the ED₉₅ seems to be the more clinically relevant value, it is seldom used to describe the anesthetic potency. The dose-response curves for inhalation anesthetic agents are steep; 1 MAC prevents skeletal muscle movement on incision in 50% of patients, whereas 1.3 MAC prevents movement in 99% of patients (ED₉₉). The dose-response curves for different inhalation anesthetic agents are parallel, implying that they share a common mechanism or site of action. This observation is supported by the fact that MAC values are additive. If 0.7 MAC N₂O is administered with 0.7 MAC isoflurane, the resulting effect is 1.4 MAC.

Factors affecting minimum alveolar concentration

Numerous physiologic and pharmacologic factors, disease states, and conditions can change the anesthetic sensitivity and, therefore, raise or lower MAC (Table 62-2). Not all the underlying mechanisms are yet clear (decrease of MAC in pregnancy or increase in redheads). Nevertheless, anesthetic requirements seem to correlate with cerebral metabolic rate, whereas factors decreasing cerebral metabolic rate (temperature, age, severe hypoxia, hypotension, various drugs) decrease MAC.

Table 62-2

Impact of Pharmacologic Agents and Physiologic Factors on Minimum Alveolar Concentration (MAC)

Decreased MAC ↓	MAC ↑
Medications
Opioids Benzodiazepines Barbiturates Propofol Ketamine α2-Agonists Intravenously administered local anesthetic agents	Inhibition of catecholamine reuptake (amphetamines, ephedrine)
Alcohol
Acute ethanol ingestion	Chronic ethanol abuse
Physiologic Conditions
Increasing age for patients >1 year of age Pregnancy	In the first months of life for infants <6 months of age
Pathophysiologic Conditions
Hypothermia Severe hypotension Severe hypoxemia Severe anemia Acute metabolic acidosis Sepsis	Hyperthermia Hyperthyroidism Increased extracellular Na⁺ in central nervous system
Genetic Factors
None established*†	Genotype related to red hair

^*Gender does not change MAC except in elderly Japanese population in whom MAC might be slightly lower in women.

^†No good data comparing MAC in different ethnic groups exist.

MAC is age dependent (Figure 62-1). The MAC value is highest in infants 3 to 6 months of age. For patients older than 1 year, MAC decreases by approximately 6% to 7% with each increasing decade of life.

Figure 62-1 Anesthetic requirements decrease with advancing age. Dose is expressed as minimum alveolar concentration (MAC) for inhalation anesthetic agents and as the relative median effective dose (ED₅₀) for intravenously administered agents. (From Muravchick S. Anesthesia for the elderly. In: Miller RD, ed. Anesthesia. 5th ed. Philadelphia: Churchill Livingstone; 2000:2140-2156.)

MAC decreases linearly with decreasing temperature; a 1° C decrease in body temperature reduces anesthetic requirement by approximately 4% to 5%. Factors that do not change MAC include duration of anesthesia, arterial blood pressure greater than 50 mm Hg, sex, and patient size.

Anesthetic requirement to blunt responses to various stimuli

The classic MAC value gives a measure of the anesthetic requirement to suppress movement to skin incision. MAC variants have been determined in an effort to define the optimal concentrations of inhalation anesthetic agents to allow for various clinically essential stimuli, such as laryngoscopy, intubation, laryngeal mask insertion, laryngeal mask removal, and extubation. The MAC variants are often depicted as multiples or fractions of the classic MAC value.

MAC_awake is the concentration of an inhaled anesthetic agent at which half of patients will open their eyes to command. It is an index of the hypnotic potency of an inhaled anesthetic agent. The knowledge of MAC_awake is helpful to prevent intraoperative awareness. The MAC_awake is approximately one third of MAC for isoflurane, desflurane, and sevoflurane but is higher for N₂O and xenon (see Table 62-1). Differences in the ratio of MAC to MAC_awake among different anesthetic agents probably reflect different mechanisms of action. The decrease of MAC_awake with age is parallel to that of MAC itself. Drugs that suppress central nervous system activity (e.g., fentanyl and clonidine) reduce the MAC_awake.

The MAC necessary to blunt the adrenergic or cardiovascular response in 50% of individuals who have a skin incision is known as the MAC_BAR. However, different harmful stimuli result in different degrees of hemodynamic responses, with intubation being more noxious than skin incision. The prevention of sympathetic stimulation and hemodynamic responses (heart rate and blood pressure increase) during surgery is especially important in patients with coronary heart disease. The MAC_BAR typically is considerably greater than the classic MAC value. This creates a conundrum for the clinician; administering a MAC_BAR to produce acceptable hemodynamic response during periods of intense surgical stimulation results in unacceptably low blood pressure during times when there is minimal stimulation. Opioids, even in small doses, and N₂O markedly decrease the MAC_BAR. This effect is the reason why N₂O and opioids are frequently coadministered with halogenated anesthetics as part of a “balanced” anesthetic.

The anesthetic concentrations that allow laryngoscopy (LS), intubation (IT), and laryngeal mask insertion (LMI) in 50% of individuals are defined as MAC_LS, MAC_IT, and MAC_LMI. The MAC_IT values are about 30% greater than the classic MAC values. The MAC_IT and MAC_LMI for sevoflurane have been extensively studied because inhaled sevoflurane is frequently used to induce anesthesia in children.

Clinical relevance

By definition, 1 MAC of an inhaled anesthetic agent alone is insufficient to provide adequate anesthesia because half of patients will respond with movement after skin incision. Nevertheless, the MAC value became the principal measure to compare the potencies of different inhalation agents. Consequently, the applied dose of an inhaled anesthetic agent often is stated in multiples or fractions of MAC. Several gas analyzers convert end-tidal concentrations of inhalation agents to MAC values; the monitor either adjusts for age and body temperature or assumes a default state of 40 years of age and a normal body temperature.

Owing to the many identified and unidentified factors affecting MAC (see Table 62-2), individual anesthetic requirements vary widely. It is therefore important to remember that MAC is an average value for a selected population rather than an absolute value for each individual.